Nanoscale drug delivery devices are a promising technology for improving drug efficacy and reducing side effects. Vesicles, which have an aqueous core bounded by a membrane, are especially useful drug delivery constructs because they can encapsulate a large aqueous-soluble payload in the vesicle core and hydrophobic payload in the membrane. The drug delivery vesicles currently in clinical use are constructed from phospholipids and synthetic polymers. However, lipids and synthetic polymers are difficult to functionalize to enable targeting and triggered release at sites of disease. The purpose of the proposed research is to engineer drug-delivery vesicles from recombinant proteins, as protein sequence can be exquisitely controlled and functional domains readily incorporated using standard molecular biology techniques. This proposal consists of three aims. The purpose of Aim 1 is to construct recombinant, unstructured, amphiphilic proteins that have distinct hydrophobic and hydrophilic domains. This will be accomplished by attaching a naturally occurring hydrophobic protein domain to an intrinsically disordered, hydrophilic protein segment. Aim 2 will test the hypothesis that this novel class of amphiphilic proteins can assemble into vesicles useful for drug delivery. Assembly will be driven by the hydrophobic effect, wherein the hydrophobic segments associate to shield themselves from water while the hydrophilic moieties face the aqueous environment. In Aim 3, the protein vesicles will be tailored for a specific biomedical application - triggered release of drugs at sites of inflammation. Inflammation is an important target because excessive inflammatory response is associated with numerous diseases, including cancer, atherosclerosis, asthma, rheumatoid arthritis, and inflammatory bowel disease. This aim will test the hypothesis that functionalizing the vesicles with a peptide that targets E-selectin, a cell adhesion molecule expressed on endothelial cells during inflammation, will cause the vesicles to adhere to activated endothelial cells in shear flow. Furthermore, specific protease cleavage sites will be incorporated into the vesicles so that proteases present at sites of inflammation will trigger vesicle rupture and drug release. Completion of the proposed work will lay the foundation for a broad new class of nanomaterials with potential for enhanced capability, tunability, and efficacy compared to existing drug delivery technologies.